EP2170848B1 - Pyrazinone derivatives and their use in the treatment of lung diseases - Google Patents

Pyrazinone derivatives and their use in the treatment of lung diseases Download PDF

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EP2170848B1
EP2170848B1 EP08776162.3A EP08776162A EP2170848B1 EP 2170848 B1 EP2170848 B1 EP 2170848B1 EP 08776162 A EP08776162 A EP 08776162A EP 2170848 B1 EP2170848 B1 EP 2170848B1
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Prior art keywords
methyl
cyclopropyl
amino
alkyl
oxo
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German (de)
English (en)
French (fr)
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EP2170848A1 (en
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Stephen Brough
Richard Evans
Timothy Jon Luker
Piotr Raubo
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AstraZeneca AB
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AstraZeneca AB
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Priority to PL08776162T priority Critical patent/PL2170848T3/pl
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Priority to HRP20141174AT priority patent/HRP20141174T1/hr
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Definitions

  • the present invention relates to pyrazinone derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • Respiratory diseases include Acute Lung Injury, Acute Respiratory Distress Syndrome (ARDS), occupational lung disease, lung cancer, tuberculosis, fibrosis, pneumoconiosis, pneumonia, emphysema, Chronic Obstructive Pulmonary Disease (COPD) and asthma.
  • ARDS Acute Respiratory Distress Syndrome
  • COPD Chronic Obstructive Pulmonary Disease
  • Asthma is generally defined as an inflammatory disorder of the airways with clinical symptoms arising from intermittent airflow obstruction. It is characterised clinically by paroxysms of wheezing, dyspnea and cough. It is a chronic disabling disorder that appears to be increasing in prevalence and severity. It is estimated that 15% of children and 5% of adults in the population of developed countries suffer from asthma. Therapy should therefore be aimed at controlling symptoms so that normal life is possible and at the same time provide basis for treating the underlying inflammation.
  • COPD is a term which refers to a large group of lung diseases which can interfere with normal breathing.
  • Current clinical guidelines define COPD as a disease state characterized by airflow limitation that is not fully reversible.
  • the airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases.
  • the most important contributory source of such particles and gases is tobacco smoke.
  • COPD patients have a variety of symptoms, including cough, shortness of breath, and excessive production of sputum; such symptoms arise from dysfunction of a number of cellular compartments, including neutrophils, macrophages, and epithelial cells.
  • the two most important conditions covered by COPD are chronic bronchitis and emphysema.
  • Chronic bronchitis is a long-standing inflammation of the bronchi which causes increased production of mucous and other changes. The patients' symptoms are cough and expectoration of sputum. Chronic bronchitis can lead to more frequent and severe respiratory infections, narrowing and plugging of the bronchi, difficult breathing and disability.
  • Emphysema is a chronic lung disease which affects the alveoli and/or the ends of the smallest bronchi.
  • the lung loses its elasticity and therefore these areas of the lungs become enlarged. These enlarged areas trap stale air and do not effectively exchange it with fresh air. This results in difficult breathing and may result in insufficient oxygen being delivered to the blood.
  • the predominant symptom in patients with emphysema is shortness of breath.
  • Corticosteroids also known as glucocorticosteroids or glucocorticoids
  • glucocorticosteroids are potent antiinflammatory agents. Whilst their exact mechanism of action is not clear, the end result of corticosteroid treatment is a decrease in the number, activity and movement of inflammatory cells into the bronchial submucosa , leading to decreased airway responsiveness. Corticosteroids may also cause reduced shedding of bronchial epithelial lining, vascular permeability, and mucus secretion. Whilst corticosteroid treatment can yield important benefits, the efficacy of these agents is often far from satisfactory, particularly in COPD.
  • a further class of therapeutic agent used in the treatment of respiratory diseases are bronchodilators.
  • Bronchodilators may be used to alleviate symptoms of respiratory diseases by relaxing the bronchial smooth muscles, reducing airway obstruction, reducing lung hyperinflation and decreasing shortness of breath.
  • Types of bronchodilators in clinical use include ⁇ 2 adrenoceptor agonists, muscarinic receptor antagonists and methylxanthines. Bronchodilators are prescribed mainly for symptomatic relief and they are not considered to alter the natural history of respiratory diseases.
  • the serine/threonine kinase, p38 is a member of the stress and mitogen activated protein kinase family (SAPK/MAPK) and participates in intracellular signalling cascades involved in a number of responses associated with inflammatory processes.
  • SAPK/MAPK stress and mitogen activated protein kinase family
  • Four isoforms of p38 kinase are known to exist, identified as p38 ⁇ , p38 ⁇ , p38 ⁇ and p38 ⁇ .
  • the p38 pathway is activated by stress (including tobacco smoke, infections or oxidative products) and pro-inflammatory cytokines (e.g. IL-1 or TNF- ⁇ ) and is involved in induction of cytokines such as TNF- ⁇ , IL-1, IL-6 and matrix metalloprotease by bacterial lipopolysaccharide (LPS).
  • cytokines e.g. IL-1 or TNF- ⁇
  • LPS bacterial lipopolysaccharide
  • Activation of p38 by dual phosphorylation of thr 180 and tyr 182 located in the activation loop is achieved by two dual specificity upstream MAP kinase kinases (MKK); MKK3 and MKK6.
  • MKK MAP kinase kinases
  • MKK3 and MKK6 MKK3 and MKK6.
  • p38 phosphorylates numerous targets including other kinases and transcription factors.
  • p38 is involved in the control of mRNA stability of several cytokines including TNF- ⁇ , IL-3, IL-6 and IL-8.
  • cytokines including TNF- ⁇ , IL-3, IL-6 and IL-8.
  • p38 kinase is thought to play a significant role in the control of transcription and translation responsible for the induction of pro-inflammatory genes and the subsequent release of pro-inflammatory cytokines such as TNF- ⁇ from cells.
  • This mechanism has been validated by investigation of the effects of inhibiting the p38 kinase enzyme on chronic inflammation and arthritis ( Kumar et al, Nature Reviews Drug Discovery (2003) 2: 717-725 ).
  • p38 kinase inhibitors have been described as potential agents for treating rheumatoid arthritis.
  • Inhibitors of p38 have been shown to inhibit LPS and ovalbumin induced airway TNF- ⁇ , IL-1- ⁇ , IL-6, IL-4, IL-5 and IL-13 ( Haddad et al Br J Pharmacol, 2001, 132 (8), 1715 ; Underwood et al., Am J Physiol Lung cell Mol 200, 279, L895 ; Duan et al., 2005 Am J Respir Crit Care Med, 171, 571 ; Escott et al Br J Pharmacol., 2000, 131, 173 ; Underwood et al., J Pharmacol Exp Ther. 293, 281 ).
  • a particular aspect of the present invention relates to pharmaceutical compositions that are formulated to allow the compounds described herein to be administered locally to the lung.
  • Advantages associated with such inhaled drug delivery include large lung surface area for dose absorption; rapid drug absorption, rapid onset of action; avoidance of the gastrointestinal tract and first-pass metabolism, lower dose and reduced side effects.
  • the present invention provides a compound of formula (I): wherein:
  • the present invention provides a prodrug of a compound of formula (I) as herein defined, or a pharmaceutically acceptable salt thereof.
  • the present invention provides an N-oxide of a compound of formula (I) as herein defined, or a prodrug or pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula (I) wherein R 1 and R 1a are H and R 2 is selected from (C 1 -C 4 )alkyl, F and Cl.
  • the present invention provides a compound of formula (I) wherein R 1 and R 1a are H and R 2 is methyl.
  • the present invention provides a compound of formula (I) wherein R 1 and R 1a are H and R 2 is selected from (C 1 -C 4 )alkyl and F.
  • the present invention provides a compound of formula (I) wherein R 1a is H, R 1 is F and R 2 is (C 1 -C 4 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 1a is H, R 1 is F and R 2 is methyl.
  • the present invention provides a compound of formula (I) wherein R 1a is H.
  • the present invention provides a compound of formula (I) wherein R 1a is H and R 1 and R 2 are independently selected from H, (C 1 -C 4 )alkyl, halo and CF 3 .
  • the present invention provides a compound of formula (I) wherein R 1a is H and R 1 and R 2 are independently selected from H, (C 1 -C 4 )alkyl and F.
  • the present invention provides a compound of formula (I) wherein R 1a is H, R 1 is selected from H and F and R 2 is selected from (C 1 -C 4 )alkyl and F. In yet another embodiment, the present invention provides a compound of formula (I) wherein R 1a is H, R 1 is H and R 2 is selected from (C 1 -C 4 )alkyl and F.
  • the present invention provides a compound of formula (I) wherein R 1a is H, R 1 is H and R 2 is methyl.
  • the present invention provides a compound of formula (I) wherein R 3 is H and R 4 is selected from H, methyl, ethyl, methoxy, ethoxy, Cl, Br, CN, phenyl and CONH 2 , wherein methyl is optionally substituted with a NR 12 R 13 group.
  • the present invention provides a compound of formula (I) wherein R 3 and R 4 are H.
  • the present invention provides a compound of formula (I) wherein R 5 is selected from NR 16 R 17 and heterocycloalkyl.
  • the present invention provides a compound of formula (I) wherein R 5 is NR 16 R 17 .
  • the present invention provides a compound of formula (I) wherein R 6 and R 7 are independently selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy and (C 3 -C 6 )cycloalkyl.
  • the present invention provides a compound of formula (I) wherein R 6 is H and R 7 is selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy and (C 3 -C 6 )cycloalkyl.
  • the present invention provides a compound of formula (I) wherein R 6 is H and R 7 is selected from methoxy (OCH 3 ), ethoxy (OCH 2 CH 3 ) and (C 3 -C 6 )cycloalkyl.
  • the present invention provides a compound of formula (I) wherein R 6 is H and R 7 is cyclopropyl.
  • the present invention provides a compound of formula (I) wherein R 16 is
  • the present invention provides a compound of formula (I) wherein R 16 is
  • the present invention provides a compound of formula (I) wherein R 16 is
  • the present invention provides a compound of formula (I) wherein R 16 is wherein R 22 and R 23 each independently represent (C 1 -C 6 )alkyl, or R 22 and R 23 together with the carbon atom to which they are attached form a (C 3 -C 7 )cycloalkyl ring.
  • the present invention provides a compound of formula (I) wherein R 17 is selected from H and (C 1 -C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 17 is H.
  • the present invention provides a compound of formula (I) wherein R 22 is selected from H, (C 1 -C 6 )alkyl, heterocycloalkyl and aryl, wherein said (C 1 -C 6 )alkyl may be optionally substituted with 1 or 2 R 28 groups.
  • the present invention provides a compound of formula (I) wherein R 22 is selected from H and (C 1 -C 6 )alkyl; wherein said (C 1 -C 6 )alkyl may be optionally substituted with a single R 28 group.
  • the present invention provides a compound of formula (I) wherein R 22 is selected from H and branched (C 1 -C 6 )alkyl; wherein said branched (C 1 -C 6 )alkyl is substituted with a single R 28 group.
  • the present invention provides a compound of formula (I) wherein R 22 is selected from H and isopropyl; wherein said isopropyl is substituted with a single R 28 group.
  • the present invention provides a compound of formula (I) wherein R 22 is selected from H and (C 1 -C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 22 is H.
  • the present invention provides a compound of formula (I) wherein R 22 is methyl.
  • the present invention provides a compound of formula (I) wherein R 23 is H.
  • the present invention provides a compound of formula (I) wherein R 23 is (C 1 -C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 23 is methyl.
  • the present invention provides a compound of formula (I) wherein X is a bond.
  • the present invention provides a compound of formula (I) wherein X is a (CR 24 R 25 ) n group and n is 1.
  • the present invention provides a compound of formula (I) wherein R 24 and R 25 are independently selected from H, OH and (C 1 -C 6 )alkyl.
  • the present invention provides a compound of formula (I) wherein R 24 and R 25 are H.
  • the present invention provides a compound of formula (I) wherein R 26 is selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, O-aryl, halo, aryl, NR 34 R 35 and CONR 34 R 35 , wherein said (C 1 -C 6 )alkyl may be optionally substituted with 1, 2, or 3 groups independently selected from halo and NR 34 R 35 .
  • the present invention provides a compound of formula (I) wherein R 26 is selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, OH, halo, aryl, NR 34 R 35 and CF 3 .
  • the present invention provides a compound of formula (I) wherein R 26 is selected from H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, OH, Cl and F.
  • the present invention provides a compound of formula (I) wherein R 27 is H.
  • the present invention provides a compound of formula (I) wherein each occurrence of R 28 is independently selected from heterocycloalkyl, halo, CF 3 , CH 2 CF 3 and NR 29 R 30 .
  • the present invention provides a compound of formula (I) wherein each occurrence of R 28 is independently selected from heterocycloalkyl and NR 29 R 30 .
  • the present invention provides a compound of formula (I) wherein R 28 is heterocycloalkyl.
  • the present invention provides a compound of formula (I) wherein Z is an aryl ring substituted with R 26 and R 27 .
  • the present invention provides a compound of formula (I) wherein Z is a phenyl ring substituted with R 26 and R 27 .
  • the present invention provides a compound of formula (I) wherein heterocycloalkyl is a C-linked or N-linked 5 or 6 membered non-aromatic, monocyclic ring, optionally fused to an aryl group, wherein said heterocycloalkyl ring contains:
  • the present invention provides a compound of formula (I) wherein halo is selected from Cl and F.
  • the present invention provides a compound of formula (I) wherein halo is F.
  • the present invention provides a compound of formula (I) wherein n is 1.
  • the present invention provides a compound of formula (IA), or a pharmaceutically acceptable salt thereof wherein:
  • the present invention provides a compound of formula (IA), wherein R 1 is selected from H and F.
  • the present invention provides a compound of formula (IA), wherein R 1 is H.
  • the present invention provides a compound of formula (IA), wherein R 1 is F.
  • the present invention provides a compound of formula (IA), wherein R 2 is methyl.
  • the present invention provides a compound of formula (IA) wherein R 1 is F and R 2 is methyl.
  • the present invention provides a compound of formula (IA), wherein R 22 and R 23 together with the carbon atom to which they are both attached form a cyclopropyl ring.
  • the present invention provides a compound of formula (IA), wherein R 22 and R 23 each independently represent methyl or ethyl.
  • the present invention provides a compound of formula (IA), wherein R 26 is (C 1 -C 6 )alkoxy substituted with NR 34 R 35 , wherein R 34 and R 35 are independently selected from H and (C 1 -C 4 )alkyl wherein said (C 1 -C 4 )alkyl may be optionally substituted by OH.
  • the present invention provides a compound of formula (IA), wherein R 26 is selected from - OCH 2 CH 2 NH 2 , -OCH 2 CH 2 NHCH 3 , -OCH 2 CH 2 NHCH 2 CH 3 , -OCH 2 CH 2 NHCH(CH 3 ) 2 , -OCH 2 CH 2 N(CH 2 CH 3 ) 2 , -OCH 2 CH 2 CH 2 NHCH 3 , -OCH 2 CH 2 CH 2 CH 2 NHCH 3 , -OCH 2 CH 2 NHCH2 C H 2 OH, -OCH 2 CH 2 N(CH 3 )CH 2 CH 2 OH, -OCH 2 CH 2 NHCH(CH 3 )CH 2 OH, -OCH 2 CH 2 NHCH 2 CH 2 CH 2 OH, and -OCH 2 CH 2 NHCH 2 CH(OH)CH 3 .
  • the present invention provides a compound of formula (IA) selected from:
  • the present invention provides a compound of formula (IA) selected from:
  • the present invention provides a compound of formula (ID), or a pharmaceutically acceptable salt thereof wherein:
  • the present invention provides a compound of formula (ID), wherein R 1 is selected from H and F.
  • the present invention provides a compound of formula (ID), wherein R 1 is H.
  • the present invention provides a compound of formula (ID), wherein R 1 is F.
  • the present invention provides a compound of formula (ID), wherein R 2 is methyl.
  • the present invention provides a compound of formula (ID), wherein R 6 is methoxy.
  • the present invention provides a compound of formula (ID), wherein R 22 and R 23 together with the carbon atom to which they are both attached form a cyclopropyl ring.
  • the present invention provides a compound of formula (ID), wherein R 22 and R 23 each independently represent methyl or ethyl.
  • the present invention provides a compound of formula (ID), wherein R 26 is (C 1 -C 6 )alkoxy substituted with NR 34 R 35 , wherein R 34 and R 35 are independently selected from H and (C 1 -C 4 )alkyl wherein said (C 1 -C 4 )alkyl may be optionally substituted by OH.
  • the present invention provides a compound of formula (ID), wherein R 26 is -OCH 2 CH 2 NHCH 3 .
  • the present invention provides a compound of formula (ID) selected from:
  • the present invention provides a compound of formula (IE), or a pharmaceutically acceptable salt thereof wherein:
  • the present invention provides a compound of formula (IE), wherein R 1 is selected from H and F.
  • the present invention provides a compound of formula (IE), wherein R 1 is H.
  • the present invention provides a compound of formula (IE), wherein R 1 is F.
  • the present invention provides a compound of formula (IE), wherein R 2 is methyl.
  • the present invention provides a compound of formula (IE), wherein R 6 is cyclopropyl.
  • the present invention provides a compound of formula (IE), wherein R 22 and R 23 together with the carbon atom to which they are both attached form a cyclopropyl ring.
  • the present invention provides a compound of formula (IE), wherein R 22 and R 23 each independently represent methyl or ethyl.
  • the present invention provides a compound of formula (IE), wherein R 34 and R 35 are independently selected from H and (C 1 -C 4 )alkyl.
  • the present invention provides a compound of formula (IE) selected from:
  • the present invention provides a compound of formula (I) selected from:
  • the present invention provides compounds of formula (IB): wherein:
  • embodiments of the invention include those wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein above in embodiments of the invention concerning compounds of formula (I).
  • the present invention provides a compound of formula (IC): wherein:
  • embodiments of the invention include those wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein above in embodiments of the invention concerning compounds of formula (I).
  • the present invention provides a compound of formula (I), (IA), (IB), (IC), (ID) or (IE) having a p38 alpha pIC 50 figure of 5.0 or greater.
  • the present invention provides a compound of formula (I), (IA), (IB), (IC), (ID) or (IE) having a p38 alpha pIC 50 figure of 6.0 or greater.
  • the present invention provides a compound of formula (I), (IA), (IB), (IC), (ID) or (IE) having a p38 alpha pIC 50 figure of 7.0 or greater.
  • the present invention provides a compound of formula (I), (IA), (IB), (IC), (ID) or (IE) having a p38 alpha pIC 50 figure of 8.5 or greater.
  • p38 alpha pIC 50 figures are determined according to the p38 alpha enzyme assay described herein below.
  • halo is selected from Cl, F, Br and I; Cycloalkyl is as defined above.
  • suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentene, cyclopenta-1,3-diene, cyclohexene and cyclohexa-1,4-diene (optionally substituted as stated above).
  • suitable cycloalkyl groups when fused with aryl, include indanyl and 1,2,3,4-tetrahydronaphthyl (optionally substituted as stated above).
  • Heterocycloalkyl is as defined above.
  • suitable heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, N-methylpiperidinyl, morpholinyl, N-methyl morpholinyl, thiomorpholinyl, thiomorpholinyl-1-oxide, thiomorpholinyl-1,1-dioxide, piperazinyl, N-methylpiperazinyl, azepinyl oxazepinyl, diazepinyl, 1,2,3,4-tetrahydropyridinyl and (optionally substituted as stated above).
  • heterocycloalkyl groups when fused with aryl or heteroaryl, include 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, tetrahydroimidazopyrazine, tetrahydroimidazopyridine and indolinyl (optionally substituted as stated above).
  • Aryl is as defined above.
  • suitable aryl groups include phenyl and naphthyl (optionally substituted as stated above).
  • Heteroaryl is as defined above.
  • suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzotriazolyl, quinolinyl and isoquinolinyl (optionally substituted as stated above).
  • alkyl, alkoxy, alkenyl and alkynyl groups containing the requisite number of carbon atoms can be branched or unbranched.
  • suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and t-butyl.
  • suitable alkoxy groups include methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy, i-propoxy, n-butoxy, sec-butoxy and t-butoxy.
  • alkenyl groups include 1,1-ethylenyl, 1,2-ethylenyl, 1,1-propylenyl, 1,2-propylenyl, 1,3-propylenyl and 2,2-propylene.
  • suitable alkynyl groups include prop-1-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl and hex-1-ynyl.
  • 'C-linked' such as in 'C-linked heterocycloalkyl', means that the heterocycloalkyl group is joined via a ring carbon atom.
  • 'N-linked' such as in 'N-linked heterocycloalkyl', means that the heterocycloalkyl group is joined via a ring nitrogen atom.
  • “Pharmaceutically acceptable salt” means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts.
  • pharmaceutically acceptable base addition salts that can be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, N -methyl-glucamine, diethanolamine or amino acids (e.g.
  • a compound of the invention contains a basic group, such as an amino group
  • pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, tosylates, benzenesulfonates, maleates, fumarates, xinafoates, p-acetamidobenzoates, succinates, ascorbates, oleates, bisulfates and the like.
  • pharmaceutically acceptable salts may include salts of pharmaceutically acceptable organic acids, especially carboxylic and sulfonic acids, including, but not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, butyrate, camphorate, camphorsulfonate, camsylate, citrate, p-chlorobenzenesulfonate, cyclopentate, 2,5-dichlorobesylate, digluconate, edisylate, esylate, fumarate, formate, gluconate, glucoheptanoate, glutamate, glutarate, glycerophosphate, glycolate, heptanoate, hexanoate, hippurate, 2-hydroxyethane sulfonate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanes
  • Salts which are not pharmaceutically acceptable may still be valuable as intermediates.
  • Hemisalts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.
  • Prodrug refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention. Suitable groups for forming pro-drugs are described in 'The Practice of Medicinal Chemistry, 2nd Ed. pp561-585 (2003 ) and in F. J. Leinweber, Drug Metab. Res., 18, 379. (1987 ).
  • the compounds of the invention can exist in both unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when the solvent is water.
  • the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically-acceptable salt thereof which comprises functionalisation of compound of formula (II) wherein R 1 , R 2 , R 3 , R 5 , R 6 and R 7 are as defined in claim 1 and L 1 is a leaving group, typically halogen, and optionally carrying out one or more of the following:
  • the functionalisation of the C 5 position of 2(1 H )-pyrazinone ring of compound of formula (II) may involve formation of a C-H, C-C, C-N, C-S or C-O bond.
  • the reaction may be catalysed by a transition metal such as palladium, or copper and conveniently performed in an organic solvent such toluene, N -methylpyrrolidin-2-one, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, ethyl acetate, N,N- dimethylformamide, N,N- dimethylacetamide, 1,2-dimethoxyethane and optionally in the presence of an appropriate base such as triethylamine, N,N -diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium tert -butoxide and at a temperature in the range, for example, of from 0 to 200°C.
  • reducing agents such as hydrogen gas, sodium formate, ammonium formate, formic acid, 1,3- or 1,4-cyclohexadiene may be used.
  • R 4 is H
  • ammonium formate in ethanol in the presence of N,N -diisopropylethylamine can be used.
  • a compound of formula (I) or a pharmaceutically-acceptable salt thereof may be prepared by reacting a compound of formula (III) wherein W 1 represents a leaving group (for example hydroxyl, alkoxy, acyloxy or halogen) with a compound of formula (IV).
  • W 1 represents a leaving group (for example hydroxyl, alkoxy, acyloxy or halogen)
  • the reaction may be carried out by treating a compound of formula (III) with a compound of formula (IV) in the presence of an organomagnesium halide, typically iso -propylmagnesium chloride or cyclopentylmagnesium bromide, or trialkylaluminium in a suitable anhydrous solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, toluene, 1,2-dimethoxyethane, and at a temperature in the range, for example, of from -78°C to ambient temperature (25°C).
  • organomagnesium halide typically iso -propylmagnesium chloride or cyclopentylmagnesium bromide
  • trialkylaluminium in a suitable anhydrous solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, toluene, 1,2-dimethoxyethane, and at a temperature in
  • reaction of (III) and (IV) may be performed under thermal conditions in in a suitable organic solvent or diluent, for example toluene, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N- dimethylformamide, N,N -dimethylacetamide, N -methylpyrrolidin-2-one at elevated temperature, for example in the range of from 40 to 130°C.
  • a suitable organic solvent or diluent for example toluene, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, N,N- dimethylformamide, N,N -dimethylacetamide, N -methylpyrrolidin-2-one at elevated temperature, for example in the range of from 40 to 130°C.
  • the carboxylic acid can be first converted to an acid halide by treatment with oxalyl halide at a temperature between -5 °C and 35 °C in an inert solvent such as dichloromethane.
  • such compounds may be prepared by hydrolysis of corresponding ester under basic (for example treating with lithium hydroxide in methanol-water mixture), hydrogenolytic (for example treating with hydrogen in appropriate solvent in the presence of palladium on charcoal) or acidic conditions (for example treating with 48% HBr or trifluoroacetic acid).
  • basic for example treating with lithium hydroxide in methanol-water mixture
  • hydrogenolytic for example treating with hydrogen in appropriate solvent in the presence of palladium on charcoal
  • acidic conditions for example treating with 48% HBr or trifluoroacetic acid.
  • Compounds of formula (II) can be prepared from the compound of formula (V) wherein W 1 represents a leaving group (for example hydroxyl, alkoxy, acyloxy or halogen), R 1 , R 2 , R 3 and R 5 as defined in the formula (I) and L 1 is a leaving group, typically halogen, using methods described for preparation of compound of formula (I) from a compound of formula (III).
  • W 1 represents a leaving group (for example hydroxyl, alkoxy, acyloxy or halogen)
  • R 1 , R 2 , R 3 and R 5 as defined in the formula (I)
  • L 1 is a leaving group, typically halogen
  • compounds of formula (III) can be conveniently prepared from the compound of formula (V) wherein W 1 represents the alkoxy group and R 1 , R 2 , R 3 , R 5 and L 1 are as defined above, using methods described for preparation of a compound of formula (I) from compound of formula (II).
  • Compounds of formula (V) can be conveniently prepared from the compound of formula (VI), wherein L 1 and L 2 are leaving groups, typically halogen, and R 1 , R 2 , R 3 are as defined above and W 1 in an alkoxy group, by selective nucleophilic aromatic substitution of the L 2 leaving group with a variety nucleophiles of formula (VII) wherein Y represents hydrogen (for example in amines, anilines, alcohols, phenols, thioalcohols, thiophenols) or a metal (for example in cyanides, Grignard reagents).
  • the reaction can be performed in a suitable organic solvent such toluene, N -methylpyrrolidin-2-one, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, ethyl acetate, N,N- dimethylformamide, N,N -dimethylacetamide, 1,2-dimethoxyethane and optionally in the presence of an appropriate base such as triethylamine, N,N -diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium carbonate, potassium carbonate, cesium carbonate, sodium tert -butoxide, sodium hydride and at a temperature in the range, for example, of from -78 to 200°C, most conveniently at ambient temperature (25°C).
  • a suitable organic solvent such toluene, N -methylpyrrolidin-2-one, tetrahydrofuran, 1,4-di
  • reaction is typically carried out in tetrahydrofuran at ambient or elevated temperature in the presence of tertiary amine such as N,N -diisopropylethylamine.
  • compounds of formula (V) where R 5 aryl, heteroaryl, alkenyl, alkynyl or CH 2 R 16 , wherein, R 16 is as defined in claim 1 can be prepared in transition metal catalysed cross-coupling reactions (for example Suzuki, Negishi, Kumada, Stille, Sonogashira, Hiyama or Heck cross-coupling reactions) from the compound of formula (VI) and formula (VII) such as alkenes, alkynes, boronic acids and esters thereof, stannanes and silanes.
  • transition metal catalysed cross-coupling reactions for example Suzuki, Negishi, Kumada, Stille, Sonogashira, Hiyama or Heck cross-coupling reactions
  • the reaction can be performed in an organic solvent such toluene, N -methylpyrrolidin-2-one, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, ethyl acetate, N,N- dimethylformamide, N,N -dimethylacetamide, 1,2-dimethoxyethane in the presence of an appropriate base such as triethylamine, N,N -diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium tert -butoxide, sodium hydride and at a temperature in the range, for example, of from 0 to 150°C.
  • an organic solvent such toluene, N -methylpyrrolidin-2-one, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, ethyl acetate, N,N- dimethylformamide, N,N -di
  • compounds of formula (VI) can be prepared from the compound of formula (IX) wherein R 1 , R 2 , R 3 are as defined above and W 1 in an alkoxy group, by treatment with suitable halogenating reagents, such as N -halosuccinimide in the presence of a base like sodium carbonate and a suitable solvent such as, for example N,N- dimethylformamide.
  • suitable halogenating reagents such as N -halosuccinimide in the presence of a base like sodium carbonate and a suitable solvent such as, for example N,N- dimethylformamide.
  • Compounds of formula (VI) can be conveniently prepared by treatment of the compound of formula (VIII) or a salt thereof, wherein R 1 , R 2 , R 3 are as defined above and W 1 is an alkoxy group, with the corresponding oxalyl halides such as oxalyl bromide or oxalyl chloride in a suitable solvent such as for example N,N- dimethylformamide, chlorobenzene, dichlorobenzene, chloroform optionally in the presence of suitable salt such as for example tetraethylammonium bromide and at a temperature in the range, for example, of from 20 to 200°C. Typically, the reaction is carried out with oxalyl bromide in 1,2-dichlorobenzene at 100°C.
  • the reaction can be performed in the presence of a non-nucleophilic base, such as N,N -diisopropylethylamine, triethylamine, sodium carbonate, in an inert solvent, such as toluene, N -methylpyrrolidin-2-one, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, ethyl acetate, N,N- dimethylformamide, N,N- dimethylacetamide and at a temperature in the range, for example, of from 0 to 150°C, preferably in tetrahydrofuran in the presence N,N -diisopropylethylamine at reflux.
  • a non-nucleophilic base such as N,N -diisopropylethylamine, triethylamine, sodium carbonate
  • an inert solvent such as toluene, N -methylpyrrolidin-2-one
  • compounds of formula (VIII) can be prepared in reaction of a compound of formula (X) with a compound of formula (XII), wherein R 3 is as defined above, and cyanides such as, for example sodium cyanide, potassium cyanide or trimethylsilyl cyanide in a suitable solvent such for example acetonitrile, acetic acid, methanol, ethanol, water, acetone, toluene optionally in the presence of suitable Lewis acid such as for example trifluoromethanesulphonic acid, magnesium sulphate, nickel chloride, zinc chloride and at a temperature in the range, for example, of from 0 to 200°C most conveniently at ambient temperature (25°C).
  • cyanides such as, for example sodium cyanide, potassium cyanide or trimethylsilyl cyanide in a suitable solvent such for example acetonitrile, acetic acid, methanol, ethanol, water, acetone, toluene optionally in the presence of suitable Lewis acid such as for example triflu
  • Compounds of formula (III) can also be conveniently prepared by treatment of a compound of formula (XIII), wherein R 1 , R 2 , R 5 are as defined above and W 1 is an alkoxy group, with a compound of formula (XIV), wherein R 3 and R 4 are as defined above, in the presence of base in a suitable organic solvent such as for example methanol.
  • Compound of formula (XVII) wherein R 22 and R 23 are as defined in claim 1 can by conveniently prepared by reacting a compound of formula (XIX) with a suitable sulfinimine in a suitable solvent, such as for example toluene, tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, dichloromethane in the presence of suitable dehydrating agent, such as for example titanium(IV) ethoxide, copper(II) sulphate, sodium(I) sulphate and at a temperature in the range, for example, of from 0 to 100°C, most conveniently at ambient temperature (25°C).
  • the reaction is carried out with (R) or (S) 2-methyl-2-propanesulfinamide in the presence of titanium(IV) ethoxide in tetrahydrofuran at ambient temperature (25°C).
  • Typical reducing agents include, for example, hydrogen gas, sodium formate, ammonium formate, formic acid, 1,3- or 1,4-cyclohexadiene.
  • the reaction may be catalysed by by a transition metal such as palladium and conveniently performed in an organic solvent such as, but not limited by, toluene, N-methylpyrrolidin-2-one, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, ethyl acetate, N,N- dimethylformamide, N,N -dimethylacetamide, 1,2-dimethoxyethane and optionally in the presence of an appropriate base such as triethylamine, N,N -diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide and at a temperature in the range, for example, of from 0 to 200°C.
  • an organic solvent such as, but not limited by, toluene, N-methylpyrrolidin-2-one, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, eth
  • reaction is carried out using Pd / C and either hydrogen gas / N,N -diisopropylethylamine or ammonium formate in ethanol at temperatures between room temperature and 80 °C.
  • Compounds of formula (XX) where W 1 is alkoxy can conveniently be prepared from (XX) where W 1 is OH by an esterification reaction. This can be carried out using the an alcohol solvent such as methanol or ethanol under for example acid catalysis.
  • Such acids can include sulfuric acid or hydrochloric acid or via addition of excess chlorotrimethylsilane and can be at a temperature in the range, for example, of from 0 to 150 °C, preferably in methanol at room temperature with excess chlorotrimethylsilane.
  • the present invention provides a process for preparing a compound of formula (I) as defined herein above, or a pharmaceutically-acceptable salt thereof, by the reaction of a compound of formula (III): wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in formula (I) and W 1 is a leaving group; with a compound of formula (IV): wherein R 6 and R 7 are as defined in formula (I).
  • the present invention further provides a compound of formula (VA) or a salt thereof wherein:
  • the present invention provides a compound of formula (VA), or a salt thereof, wherein W 1 is OH or OMe; R 1 is H or F; R 2 is methyl; R 4 is H or Br; R 22 and R 23 each independently represent methyl, or R 22 and R 23 together with the carbon atom to which they are both attached form a cyclopropyl ring; and R 26 is OH, OCH 2 Ph or OCH 2 CH 2 Cl.
  • the present invention further provides a compound of formula (VIA) or a salt thereof wherein:
  • the present invention provides a compound of formula (VIA), or a salt thereof, wherein W 1 is OH or OMe; R 1 is H or F; and R 2 is methyl.
  • the present invention provides the compound (XXI), or a salt thereof,
  • the compounds of the invention have activity as pharmaceuticals, in particular as p38 kinase inhibitors.
  • Diseases and conditions which may be treated with the compounds include:
  • the present invention further provides a compound of formula (I), (IA), (IB), (IC), (ID) or (IE) as as hereinbefore defined, or a pharmaceutically acceptable salt thereof, for use in therapy.
  • the invention provides the use of a compound of formula (I), (IA), (IB), (IC), (ID) or (IE) as as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be construed accordingly.
  • the present invention also provides the use of a compound of formula (I), (IA), (IB), (IC), (ID) or (IE) as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease (COPD) (such as irreversible COPD).
  • COPD chronic obstructive pulmonary disease
  • the present invention also provides a compound of formula (I), (IA), (IB), (IC), (ID) or (IE) as hereinbefore defined, or a pharmaceutically acceptable salt thereof, for treating COPD.
  • the present invention also provides the use of a compound of formula (I), (IA), (IB), (IC), (ID) or (IE) as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of asthma.
  • the present invention also provides a compound of formula (I), (IA), (IB), (IC), (ID) or (IE) as hereinbefore defined, or a pharmaceutically acceptable salt thereof, for treating asthma.
  • a compound of the invention for the therapeutic treatment of a warm-blooded animal, such as man, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition that comprises a compound of the invention as hereinbefore defined and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition will, for example, comprise from 0.05 to 99%w (per cent by weight), such as from 0.05 to 80%w, for example from 0.10 to 70%w, such as from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
  • topical such as to the lung and/or airways or to the skin
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule, which contains between 0.1 mg and 1g of active ingredient.
  • a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg -1 to 100mgkg -1 of the compound, for example in the range of 0.1mgkg -1 to 20mgkg -1 of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose, which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day
  • Another suitable pharmaceutical composition of this invention is one suitable for inhaled administration, inhalation being a particularly useful method for administering the compounds of the invention when treating respiratory diseases such as chronic obstructive pulmonary disease (COPD) or asthma.
  • COPD chronic obstructive pulmonary disease
  • the compounds of formula (I) may be used effectively at doses in the ⁇ g range, for example 0.1 to 500 ⁇ g, 0.1 to 50 ⁇ g, 0.1 to 40 ⁇ g, 0.1 to 30 ⁇ g, 0.1 to 20 ⁇ g, 0.1 to 10 ⁇ g, 5 to 10 ⁇ g, 5 to 50 ⁇ g, 5 to 40 ⁇ g, 5 to 30 ⁇ g, 5 to 20 ⁇ g, 5 to 10 ⁇ g, 10 to 50 ⁇ g, 10 to 40 ⁇ g 10 to 30 ⁇ g, or 10 to 20 ⁇ g of active ingredient.
  • a pharmaceutical composition comprising a compound of the invention as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier, which is formulated for inhaled administration.
  • metered dose inhaler devices When administered by inhalation, metered dose inhaler devices may be used to administer the active ingredient, dispersed in a suitable propellant and with or without additional excipients such as ethanol, surfactants, lubricants or stabilising agents.
  • Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (e.g. heptafluoroalkane) propellants, or mixtures of any such propellants.
  • Preferred propellants are P134a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients.
  • Nebulised aqueous suspensions or, preferably, solutions may also be employed, with or without a suitable pH and/or tonicity adjustment, either as a unit-dose or multi-dose formulations.
  • Dry powder inhalers may be used to administer the active ingredient, alone or in combination with a pharmaceutically acceptable carrier, in the later case either as a finely divided powder or as an ordered mixture.
  • the dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
  • Metered dose inhaler, nebuliser and dry powder inhaler devices are well known and a variety of such devices are available.
  • the invention further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.
  • the compounds of the invention may be combined with agents listed below.
  • Non-steroidal anti-inflammatory agents including non-selective cyclo-oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramus
  • the present invention still further relates to the combination of a compound of the invention together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin-like growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF- ⁇ ) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.
  • a cytokine or agonist or antagonist of cytokine function including agents which act on cytokine signalling pathways such as modulators of the SOCS system
  • the invention relates to a combination of a compound of the invention with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA-aILI6R and T-Lymphocytes, CTLA4-Ig, HuMax II-15).
  • B-Lymphocytes such as CD20 (rituximab), MRA-aILI6R and T-Lymphocytes, CTLA4-Ig, HuMax II-15.
  • the present invention still further relates to the combination of a compound of the invention with a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CR1 for the C-X 3 -C family.
  • a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX 3 CR1 for the C-X 3
  • the present invention further relates to the combination of a compound of the invention with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.
  • MMPs matrix metalloprotease
  • the present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.
  • the present invention further relates to the combination of a compound of the invention and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-1s such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.
  • LT leukotrienes
  • the present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.
  • PDE phosphodiesterase
  • the present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.
  • a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine
  • the present invention still further relates to the combination of a compound of the invention and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.
  • a proton pump inhibitor such as omeprazole
  • a gastroprotective histamine type 2 receptor antagonist such as a gastroprotective histamine type 2 receptor antagonist.
  • the present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.
  • the present invention still further relates to the combination of a compound of the invention and an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.
  • an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, t
  • the present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an anticholinergic agent including a muscarinic receptor (M1, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • M1, M2, and M3 antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.
  • the present invention still further relates to the combination of a compound of the invention and a beta-adrenoceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, or indacaterol or a chiral enantiomer thereof.
  • a beta-adrenoceptor agonist including beta receptor subtypes 1-4
  • the present invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.
  • a chromone such as sodium cromoglycate or nedocromil sodium.
  • the present invention still further relates to the combination of a compound of the invention with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • a glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.
  • the present invention further relates to the combination of a compound of the invention with an agent that modulates a nuclear hormone receptor such as PPARs.
  • the present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • Ig immunoglobulin
  • Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).
  • anti-IgE for example omalizumab
  • the present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.
  • the present invention still further relates to the combination of a compound of the invention and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine
  • immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.
  • the present invention further relates to the combination of a compound of the invention together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfinavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine
  • the present invention still further relates to the combination of a compound of the invention and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.
  • a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist
  • ACE angiotensin-converting enzyme
  • angiotensin-2 receptor antagonist angiotensin-2 receptor antagonist
  • a lipid lowering agent such as a statin or a fibrate
  • a modulator of blood cell morphology such as pentoxyfylline
  • the present invention further relates to the combination of a compound of the invention and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.
  • a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropini
  • the present invention still further relates to the combination of a compound of the invention and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agents, paracetamol, or a non-steroidal anti-inflammatory agent.
  • analgesic for example an opioid or derivative thereof
  • carbamazepine for example an opioid or derivative thereof
  • phenytoin for example an opioid or derivative thereof
  • sodium valproate for example an opioid or derivative thereof
  • amitryptiline or other anti-depressant agents for example an opioid or derivative thereof
  • paracetamol for example an opioid or derivative thereof
  • non-steroidal anti-inflammatory agent for example an opioid or derivative thereof
  • the present invention further relates to the combination of a compound of the invention together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.
  • a compound of the present invention can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.
  • a hormonal agent such as raloxifene
  • a biphosphonate such as alendronate.
  • the present invention still further relates to the combination of a compound of the invention together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate de
  • -receptor antagonist for example colchicine
  • anti-gout agent for example colchicine
  • xanthine oxidase inhibitor for example allopurinol
  • uricosuric agent for example probenecid, sulfinpyrazone or benzbromarone
  • growth hormone secretagogue for example transforming growth factor (TGF ⁇ );
  • PDGF platelet-derived growth factor
  • fibroblast growth factor for example basic fibroblast growth factor (bFGF);
  • GM-CSF granulocyte macrophage colony stimulating factor
  • capsaicin cream for example tachykinin NK1 or NK3 receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418;
  • elastase inhibitor such as UT-77 or ZD-0892
  • TNF-alpha-1 for example colchicine
  • xanthine oxidase inhibitor for example allopurinol
  • uricosuric agent for example
  • a compound of the invention can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:
  • the present invention provides a pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I), (IA), (IB), (IC), (ID) or (IE) as hereinbefore described, or a pharmaceutically acceptable salt thereof, and at least one further active ingredient selected from:-
  • the pharmaceutical product according to this embodiment may, for example, be a pharmaceutical composition comprising the first and further active ingredients in admixture.
  • the pharmaceutical product may, for example, comprise the first and further active ingredients in separate pharmaceutical preparations suitable for simultaneous, sequential or separate administration to a patient in need thereof.
  • the pharmaceutical product of this embodiment is of particular use in treating respiratory diseases such as asthma, COPD or rhinitis.
  • Examples of a phosphodiesterase inhibitor that may be used in the pharmaceutical product according to this embodiment include a PDE4 inhibitor such as an inhibitor of the isoform PDE4D, a PDE3 inhibitor and a PDE5 inhibitor. Examples include the compounds
  • Examples of a ⁇ 2 -adrenoceptor agonist that may be used in the pharmaceutical product according to this embodiment include metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol (e.g. as sulphate), formoterol (e.g. as fumarate), salmeterol (e.g. as xinafoate), terbutaline, orciprenaline, bitolterol (e.g. as mesylate), pirbuterol or indacaterol.
  • the ⁇ 2 -adrenoceptor agonist of this embodiment may be a long-acting ⁇ 2 -agonists, for example salmeterol (e.g.
  • Examples of a modulator of chemokine receptor function that may be used in the pharmaceutical product according to this embodiment include a CCR1 receptor antagonist.
  • protease inhibitor examples include an inhibitor of neutrophil elastase or an inhibitor of MMP12.
  • Examples of a steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include budesonide, fluticasone (e.g. as propionate ester), mometasone (e.g. as furoate ester), beclomethasone (e.g. as 17-propionate or 17,21-dipropionate esters), ciclesonide, loteprednol (as e.g. etabonate), etiprednol (as e.g. dicloacetate), triamcinolone (e.g.
  • a muscarinic receptor antagonist for example a M1, M2 or M3 antagonist, such as a M3 antagonist
  • ipratropium e.g. as bromide
  • tiotropium e.g. as bromide
  • oxitropium e.g. as bro
  • a quinuclidine derivative such as 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2]octane bromide as disclosed in US 2003/0055080 , quinuclidine derivatives as disclosed in WO 2003/087096 and WO 2005/115467 and DE 10050995 ; or GSK 656398 or GSK 961081.
  • Examples of a modulator of a non-steroidal glucocorticoid receptor agonist that may be used in the pharmaceutical product according to this embodiment include those described in WO2006/046916 .
  • the NMR spectra were measured on a Varian Unity Inova spectrometer at a proton frequency of either 300 or 400 MHz. Reactions that were heated by microwace irradiation were pereperformed using a CEM Discover Microwave. Examples having chiral centre might appear in NMR as a mixture of rotamers.
  • the MS spectra were measured on either an Agilent 1100 MSD G1946D spectrometer or a Hewlett Packard HP1100 MSD G1946A spectrometer.
  • Preparative HPLC separations were performed using a Waters Symmetry ® or Xterra ® column or Phenomenex Gemini ® using 0.1% aqueous trifluoroacetic acid: acetonitrile, 0.1% aqueous ammonia: acetonitrile or 0.1% ammonium acetate: acetonitrile as the eluent.
  • SCX and NH 2 resin were obtained from Varian Incorporated.
  • Compound names were generated using the commercially available chemical naming software package Index ACDLABS 8.0.
  • the reaction was heated within a microwave at 120°C for 60 minutes before cooling to room temperature and adding cyclopropylamine (150 ⁇ L) and cyclopentylmagnesium bromide (2M in diethyl ether, 0.75 mL) portionwise After stirring for 30 minutes, ethanol (2 mL) was added followed by the addition of ammonium formate (0.3 g) and 10% palladium on carbon (30 mg). The mixture was heated within a microwave for 180 minutes at 100°C before being cooled to room temperature, filtered and washed with ethanol. The filtrate was concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound (19 mg).
  • the reaction was cooled to room temperature followed by the addition of ammonium formate (0.4 g), 10% palladium on carbon (30 mg), formic acid (0.2 mL) and ethanol (1 mL).
  • the reaction mixture was heated within a microwave for 60 minutes at 100°C before being cooled to room temperature.
  • Water was added and the mixture extracted with ethyl acetate.
  • the pooled organic were washed with water, dried (Na 2 SO 4 ), filtered and concentrated.
  • the product was taken up in tetrahydrofuran (4 mL) followed by the addition of cyclopropylamine (0.22 mL) and cyclopentylmagnesium bromide (2M in diethyl ether, 1.5 mL) dropwise.
  • 1,4-Cyclohexadiene (1 mL) was added and the mixture was heated under atmosphere of nitrogen within a microwave for 10 minutes at 90°C before being cooled to room temperature. The mixture was filtered and concentrated. The residue was treated with tetrahydrofuran (10 mL), water (2 mL) and lithium hydroxide (193 mg). The mixture was stirred for 2 h, diluted with ethyl acetate, washed with 2M hydrochloric acid and water. The organic phase was dried (Na 2 SO 4 ) and concentrated.
  • Example 126 and Example 127
  • 1,4-Cyclohexadiene (2 mL) was added and the mixture was heated under atmosphere of nitrogen within a microwave for 15 minutes at 90°C before being cooled to room temperature. The mixture was filtered and concentrated to give a crude product that was used in the next step without purification.
  • Example 128a The title compound was prepared from of 4-methyl-3-(2-oxo-3-phenoxy-1 (2H)-pyrazinyl)-benzoic acid, methyl ester (Example 128a) and 2-chlorobenzenemethanamine using the method described for Example 128. MS: APCI(+ve) 409 (M+H + ).
  • Example 128a The title compound was prepared from 4-methyl-3-(2-oxo-3-phenoxy-1 (2H)-pyrazinyl)-benzoic acid, methyl ester (Example 128a) and 3-chlorobenzenemethanamine using the method described for Example 128.
  • the reaction mixture was cooled to room temperature and quenched with sat. NaHCO 3 .
  • the mixture was extracted with dichloromethane.
  • the pooled organics were washed with water and brine, dried (Na 2 SO 4 ), filtered and the solvent removed.
  • the product was taken up in tetrahydrofuran (3 mL) followed by the addition of cyclopropylamine (0.15 mL) and cyclopentylmagnesium bromide (2M in diethyl ether, 0.75 mL) portionwise.
  • the reaction mixture was stirred under nitrogen for 1 h before the addition of ethanol (2 mL), ammonium formate (300 mg) and 10% palladium on carbon (30 mg).
  • N -cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2 H )-yl)-4-methylbenzamide (Example 134, 0.1 g) in N,N -dimethylformamide (3 mL), N -(2-chloroethyl)-pyrrolidine, hydrochloride (0.12 g) and cesium carbonate (0.47 g) were added. The reaction was stirred under nitrogen at 80°C for 12 h.
  • the organic phase was separated, dried (Na 2 SO 4 ), filtered through a pad of Celite and concentrated in vacuo to give the crude sulfinimine, which was dissolved in dry dichloromethane (90 mL) and the solution was cooled to -50°C.
  • a solution of phenylmagnesium bromide in diethyl ether (3M, 13 mL) was added dropwise and the reaction mixture was warmed up to 0°C over 3 h, quenched with sat. aqueous NH 4 Cl (150 mL) and extracted into dichloromethane.
  • the organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • Example 136a The title compound was prepared from (2 S )-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]- N- methoxy- N ,2-dimethyl-propanamide (Example 136a) and 1-naphthalenylmagnesium bromide using methods described in the Example 136a and 136b.
  • Examples 139-157 (Table 3) were prepared from the corresponding alcohols and amines using the general procedure described for Example 138b (in some reactions a mixture of diasteroisomers was obtained. Isomers were separated by preparative HPLC).
  • the subtitle compound was prepared from 3-[3-[[(1 R ,2 R )-3-hydroxy-2-methyl-1-(1-naphthalenyl)propyl]amino]-2-oxo-1 (2H)-pyrazinyl]-4-methyl-benzoic acid, methyl ester (Example 137a) using the method described in Example 138a.
  • the subtitle compound was prepared from 4-methyl-3-[3-[[(1 R ,2 R )-2-methyl-1-(1-naphthalenyl)-3-oxopropyl]amino]-2-oxo-1 (2H)-pyrazinyl]-benzoic acid, methyl ester (Example 158a) using the method described in the Example 138b.
  • Examples 159-161 were prepared from corresponding alcohols (Examples 136c or 137a) and amines using the method described for Example 158.
  • Methanesulfonyl chloride (0.21 mL) was added to a stirred solution of N-cyclopropyl-3-[3-[[(1 R )-1-[2-(2-hydroxyethoxy)phenyl]propyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (410 mg) and triethylamine (0.5 mL) in dichloromethane (10 mL) at 0°C. The mixture was stirred for 1 h at 0°C and 1 h at room temperature. Water was added and the organic phase was separated, (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • Example 165a The title compound was prepared from ( S) -2-methyl- N -[(1 S )-1-[2-(2-hydroxyethoxy)phenyl]propyl]-2-propanesulfinamide (Example 165a) using the method described for Example 165b and 165c. MS: APCI(+ve) 516 (M+H + ).
  • Titanium(IV) isopropoxide (1.62 mL) was added to a stirred solution of 2-(benzyloxy)benzonitrile (1.05 g) in diethyl ether (25 mL) cooled to -78 °C under N 2 followed by the dropwise addition of ethylmagnesium bromide (3.67 mL of a 3M solution in diethylether). The resulting mixture was stirred at -78 °C for 10 min and then warmed to rt over 1 h. Boron trifluoride diethyl etherate (1.27 mL) was added dropwise and the mixture was stirred for 1 h. The reaction was quenched with 1 M HCl (30 mL).
  • the title product was prepared from 3-[3-[[1-[2-(2-chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2 H )-pyrazinyl]- N -cyclopropyl-5-fluoro-4-methyl-benzamide (Example 169h) and methylamine using a similar method to that described for example 167f. Purification was by RPHPLC (0.2% ammonia/ MeCN gradient on a Phenominex column).
  • Example 170-197 were prepared from the corresponding alcohol (Example 136d) and amines using the methods described for Example 138.
  • the subtitle compound was prepared by using ⁇ , ⁇ -dimethyl-2-(phenylmethoxy)-benzenemethanamine (Example 198d) using the methods described in example 134 to give N -cyclopropyl-4-methyl-3-[3-[[1-methyl-1-[2-[2-(1-pyrrolidinyl)ethoxy]phenyl]ethyl]amino]-2-oxo-1(2 H )-pyrazinyl]-benzamide which was alkylated with 1-bromo-2-chloroethane as described in example 167e to afford the subtitle product.

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